1. Field of the Invention
The present invention is directed to L-DOPA type compounds and more specifically, to certain novel, transient, pro-drug forms of L-DOPA, capable of administration to warm-blooded animals.
As employed in this application, the expression "pro-drug" denotes a derivative of a known and proven prior art compound, which derivative, when absorbed into the bloodstream of a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form and permit the same to attain a higher bioavailability level than that which could be obtained if the proven drug form per se was administered.
Furthermore, as used in this application, the term "transient" denotes "cleavage" of the compounds of this invention in such a manner that the proven drug form is released and the remaining "cleaved" moiety is non-toxic and metabolized in such a manner that non-toxic, metabolic products are produced.
2. Description of the Prior Art
L-DOPA (3,4-dihydroxy-L-phenylalanine) is presently, generally accepted as the primary drug of choice in the treatment of Parkinson's Disease. However, due to its extensive extracerebral metabolism, extremely large doses (up to 8 grams) of this drug are required to initiate a medically acceptable therapeutic effect. Such large doses often cause intolerable side effects, such as gastro-intestinal symptoms (anorexia, nausea, and vomiting), orthostatic hypotension, and the development of involuntary movements. See, D. B. Calne, Clin. Pharmac. Ter., 11, 789 (1971). While decreasing the daily dose of L-DOPA would eliminate the above-described side effects, nevertheless, Parkinsonism symptons will return.
It has been known that a significant percentage of the amount of L-DOPA in contact with the gastric mucosa is metabolized (L. Rivera-Calimlim, C. A. Dujovane, J. P. Morgan, L. Lasagna, and J. R. Bianchine, Europ. J. Clin. Invest., 1, 313 (1971). This may delay and lower the attainable peaks of unchanged L-DOPA in the blood serum, which may be a critical factor for the passage of L-DOPA into the brain. Although, possibly, some metabolism of L-DOPA can occur in the human intestine, it would be expected to be minimal, because L-DOPA appears to be more rapidly absorbed in the intestine. On the other hand, L-DOPA, once delivered to the bloodstream by any suitable route (orally) is rapidly and continuously metabolized, since only 5.0 to 8.0 percent of L-DOPA is protein bound. Consequently, L-DOPA is very susceptible to metabolic processes. See, H. Hinterberger, Biochem. Med., 5, 412 (1971).
The metabolism of L-DOPA can occur through a wide variety of metabolic pathways. The main initial steps are decarboxylation, 3-O-methylation, or transamination. L-DOPA appears to be metabolized within the brain in the same manner, as it is extracerebally metabolized. The necessary enzymes required to achieve these metabolisms, are DOPA-decarboxylase, COMT and MAO. These enzymes are well-known and widely distributed in man, including the liver, kidney, heart, and brain.
Due to the short half-life of L-DOPA in the bloodstream (approximately 45 minutes) as determined by C. B. Coutinaho, H.E. Spiegel, et al., J. Pharm. Sci., 60, 1014 (1971) and B. Weiss, and G. V. Rossi, Biochem Pharmacol., 12, 1399 (1963), and further due to its excessive metabolism prior to distribution in the bloodstream, a means of increasing L-DOPA blood levels without increasing L-DOPA dosage becomes exceedingly necessary.
The initial approach to this problem resides in decreasing the stomach elimination time, usually through the use of antacids, which appear to decrease gastric distress and result in somewhat higher L-DOPA blood levels. See, J. R. Bianchine, L. Rivera-Calimlin, C. A. Dujovene, J. P. Morgan, and L. Lasagne, Ann. N.Y. Acad. Sci., 179, 126 (1971).
In other instances, the employment of decarboxylase inhibitors appear to provide some improvement. For example, reference is made to the articles by A. Pletscher and C. Bartholini, Clin. Pharmac. Ther., 12, 344 (1971); D. L. Dunner, H.U.H. Brodie, and F. K. Goodwin, Ibid, 12, 212 (1971); and A. Barbeau, L. Gillo-Goffrey and H. Mars, Ibid, 12, 353 (1971).
With respect to the above, the most potent decarboxylase inhibitors are those of the hydrazine type, such as RO4-4602 [N-(D,L-Seryl)-N'-(2,3,4-trihydroxybenzyl)-hydrazine] and MK-486 (alphamethyl-dopa-hydrazine). By employing these inhibitors, relatively small dosages of L-DOPA will provide therapeutic blood levels; however, the patient may be subjected to toxic effects as a result of such inhibitors.
It has also been found that the co-administration of COMT (catechol-O-methyl-transferase) inhibitors can also result in an increase in the free L-DOPA blood level. See, R. D. Robson, N.J. Antonaccio, and R. K. Reinhart, Europ. J. Pharmacol., 20, 104 (1972) and R. J. Valdessarini, and E. Greiner, Biochem. Pharmacol., 22, 247 (1973). With reference to these articles, it was determined that L-DOPA can severely tax normal methylation processes and therefore, interfere with methylation of biologically important substances. Moreover, it has also been determined that L-DOPA can increase blood concentrations of SAMe (s-adenosyl-methionine) in patients treated.
Therefore, it follows that blocking the methylation of L-DOPA might enhance bioavailability thereof, decrease the formation of methylated metabolites and further prevent the occurrence of side effects associated with L-DOPA.
It has been demonstrated that the COMT inhibitors, do indeed aid in the reduction of the therapeutic dose required for L-DOPA. However, most of the available COMT inhibitors, including pyrogallol, desmethylpapaverine, tropolones, catecholacetamides, gallic acid esters, and substituted benzoates are of limited utility because of their lack of potency and duration of action, or in the alternative, simply due to their extreme toxicity.
Recently, U.S. Pat. No. 3,803,120 issued disclosing and claiming certain unprotected di- and tri-peptides of L-DOPA. While the patentee does disclose fully unprotected di- and tri-peptides of L-DOPA, therapeutically active protected di- and tri-peptides of L-DOPA are not at all suggested. As indicated earlier, the essence of this invention relies on the fact that three sites of unwanted metabolism are present on the L-DOPA molecule. Consequently, according to this invention, these metabolic sites are protected during and/or prior to the absorption process. In this manner, degradation of the L-DOPA molecule will not occur at a point in time where it would hinder the attainment of L-DOPA bioavailability. Evidence of the superior advantage attained with protecting the L-DOPA molecule in this manner is easily gathered from a review of Table I of this application. In all instances, the protected L-DOPA compounds of this invention enabled L-DOPA to obtain superior bioavailability levels in comparison to that obtained when L-DOPA was administered per se. Granted, the patentee does disclose a protected L-DOPA molecule in numerous instances, but in each of these instances, it is for the sole purpose of protecting the L-DOPA molecule during synthesis. That is, the protected L-DOPA compounds of the patentee are useful as intermediates only. This is further buttressed by the fact that the patentee specifically teaches that only compounds of the formula (I) through (IV) and (XX) have any anti-Parkinsonism activity at all. The compounds encompassed within the aforementioned formulas of the patentee do not represent fully protected L-DOPA compounds as is the case with the instant invention. See also, "Synthesis and Antireserpine Activity of Peptides of L-DOPA", Arthur M. Felix, et al., J. Med. Chem., 17, No. 4, 422 (1974).